The present invention relates to radiological imaging systems, and more particularly to use of a contrast enhancing agent in imaging parts of an animal body according to methods of magnetic resonance imaging (MRI), computed tomography (CT), or conventional radiography (X-ray).
Contrast agents are useful adjuncts in radiological imaging procedures because they make it possible to determine the location, size and conformation of organs or other structures of the body in the context of their surrounding tissues.
Cells which make up the tissues of soft non-bony body parts are comprised primarily of water even among parts that differ markedly in shape and structure such as the liver, pancreas and intestine. Radiography procedures of computed tomography and magnetic resonance imaging operate on the basis of distinct physical principles, but each detects and maps differences in the composition of a target object; therefore these procedures often fail to provide satisfactory images of contiguous body parts without the aid of a contrast agent. In the diagnosis of disorders of the digestive tract, for example, blockage or abnormalities in the conformation of loops of intestine lying one on the other are difficult to identify unless the section of the gastrointestinal tract is filled with a contrast agent to define volumes and delineate boundaries.
In the conventional radiographic procedure, a beam of x-rays passes through a target object and exposes an underlying photographic film. The developed film then provides a image of the radiodensity pattern of the object. Less radiodense areas produce a greater blackening of the film; more radiodense, bony tissues produce a light image. Effective contrast agents for x-ray may be either less radiodense than body tissues or may be more radiodense. The less radiodense agents comprise air or another gas. For example, a patient may be assisted to swallow air in order to better visualize the upper gastrointestinal tract, or air may be introduced into the ventricles of the brain in procedures to visualize these structures. An example of a more radiodense contrast material is a barium sulfate suspension which is commonly introduced into the bowel prior to radiographic imaging.
Computed tomography (CT) is superior to conventional radiography in its ability to image a succession of thin sections of an object at specific points, lines or planes along the X, Y or Z axis of the target object and to do this with extremely high resolution; but because this procedure is also based on the detection of differences in radiodensity, requirements for contrast agents in computed tomography are identical with those for conventional radiography.
Nuclear magnetic resonance imaging (MRI) systems for body imaging operate on a different physical principle. Literature describing the theoretical and practical use of MRI systems are available from manufacturers such as the General Electric & Co. who market commercial systems. A general reference on the background and theoretical description of the MRI system, the publication entitled "NMR Tomography" by William G. Bradley (1982), is available from Diasonics, Inc., Milpitas, Calif., and is attached hereto as an appendix and incorporated herein for convenience.
In the magnetic resonance imaging systems, advantage is taken of the fact that some atomic nuclei, such as, for example, hydrogen nuclei, have both nuclear spin and nuclear magnetic moment, and therefore can be manipulated by applied magnetic fields. In the customary type of MRI system, a magnetic field is established across a body to align the spin axes of the nuclei of a particular chemical element, usually hydrogen, with the direction of the magnetic field. The aligned, spinning nuclei execute precessional motions around the aligning direction of the magnetic field. For the aligned, spinning nuclei, the frequency at which they precess around the direction of the magnetic field is a function of the particular nucleus which is involved and the magnetic field strength. The selectivity of this precessional frequency with respect to the strength of the applied magnetic field is very sharp and this precessional frequency is considered a resonant frequency.
In a customary MRI system, after alignment or polarization of the selected nuclei, a burst of radio frequency energy at the resonant frequency is radiated at the target body to produce a coherent deflection of the spin alignment of the selected nuclei. When the deflecting radio energy is terminated, the deflected or disturbed spin axes are reoriented or realigned, and in this process radiate a characteristic radio frequency signal which can be detected by an external coil and then discriminated in the MRI system to establish image contrast between different types of tissues in the body. MRI systems have a variety of different excitation and discrimination modes available, such as, for example, free induction decay ("FID"), spin echo, continuous wave, which are known in the art.
Two parameters are used to measure the response of the magnetized sample to a disturbance of its magnetic environment. One is T.sub.1 or "thermal" relaxation time, the time it takes the sample to become magnetized or polarized after being placed in a external magnetic field; the other is T.sub.2, the spin-spin relaxation time, a measure of the time the sample holds a temporary transverse magnetization which is perpendicular to the external magnetic field. Images based on proton density can be modified by these two additional parameters to enhance differences between tissues.
Hydrogen has been usually selected as the basis for MRI scanning because of its abundance in the water content of the body and its prominent magnetic qualities. It is believed that investigations are being conducted to determine if sodium and phosphorous would also be satisfactory as the basis for magnetic resonance imaging.
Contrast agents for MRI must posses a substantially different concentration of the nuclei used as a basis for scanning. In a hydrogen scanning system, an agent substantially lacking hydrogen can be used; in an MRI system which scans for a physiologically minor nucleus, for example, the fluorine nuclei, a substance with a high concentration of that nucleus would provide appropriate contrast.
Contrast agents may be introduced into the body space in various ways depending on the imaging requirement. In the form of liquid suspensions or emulsions they may be placed in the gastrointestinal tract by oral ingestion or by rectum, inserted into bodily spaces like the peritoneal cavity or injected into the vascular system either generally or into the vessels of a specific organ such as the coronary artery.
A suitable contrast agent must be biocompatible, that is non-toxic and chemically stable, not absorbed by the body or reactive with the tissue, and eliminated from the body within a short time. Few satisfactory agents have been developed for MRI. Imaging of the gastrointestinal tract of animals has been enhanced with large doses of mineral oil. (Newhouse, J. R., et al: Abdominal NMR Imaging: Normal Anatomy, Fluid Collections and a New Contrast Agent, presented at 67th Scientific Assembly of RSNA, Chicago, Ill., Nov. 15-20, 1981). Magnesium cations have been used in the study of experimental myocardial infarction, (Rydder G. M.: Clinical NMR Results from Second Nuclear Magnetic Imaging Symposium. Winston-Salem, N.C. 1981 (in press)). Inhaled oxygen can also provide contrast in the heart (Young I. R., et al., Initial Clinical Evaluation of Whole Body NMR Tomograph. J. of Comput. Assist. Tomograph. 6:1-18. February 1982).
lt is known to use perfluorocarbons, including brominated perfluorocarbons, as a contrast enhancement medium in radiological imaging as shown in U.S. Pat. No. 3,975,512 to Long, the applicant herein. Brominated and other fluorocarbons are known to be safe and biocompatible when used internally in the body. It is also known to use these agents in the context of the MRI procedure to contrast more clearly and more distinctly in MRI-produced images the several body parts which normally have substantially higher water content and which are close or overlaid one on the other.
It is desirable to provide other compounds of this class which can be used even more safely, more efficiently, and more economically. It is therefore an object of the invention to provide contrast agents which are even less readily absorbed by the body and operate in such a manner as to reduce the total amount of material necessary to provide a satisfactory radiological or magnetic resonance image.